The invention relates to sulfonyloxazolamines of the general formula I and to their use as medicaments, and to a process for their preparation, to the intermediates employed in the preparation process and to a process for preparing the intermediates.
The sulfonyloxazolamines according to the invention are compounds of the general formula (I) 
where
R1 and R2 independently of one another are H, xe2x80x94R6, xe2x80x94C3-C8-cycloalkyl, xe2x80x94(CH2)nxe2x80x94R7, xe2x80x94(CH2)nxe2x80x94Oxe2x80x94R6, xe2x80x94(CH2)nxe2x80x94NH2, xe2x80x94(CH2)nxe2x80x94NHR6, xe2x80x94(CH2)xe2x80x94N(R6)2, C2-C6-alkenyl or, where appropriate, together form a mononuclear saturated heterocycle having one or two nitrogen, oxygen and/or sulfur atoms,
R3 and R4 independently of one another are H, xe2x80x94R6, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94Hal, xe2x80x94OH, xe2x80x94Oxe2x80x94R6, xe2x80x94NH2, xe2x80x94NHxe2x80x94R6 or xe2x80x94N(R6)2,
R5 is a 5- or 6-membered, saturated or unsaturated heterocycle having one or two nitrogen, oxygen and/or sulfur atoms which may be mono- or disubstituted by xe2x80x94R6, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94Hal, xe2x80x94OH, xe2x80x94Oxe2x80x94R6, xe2x80x94NH2, xe2x80x94NHxe2x80x94R6 or xe2x80x94N(R6)2, and
R6 is C1-C6-alkyl,
R7 is R3- and/or R4-substituted phenyl,
n is 0 to 2,
and physiologically acceptable salts or solvates thereof.
Some sulfonyloxazolamines are known from various earlier publications: V. A. Chervonyi et al., Ukr. Khim. Zh. (Russian Ed.) 1991, 57(4), 415-418 or V. A. Chervonyi et al., Zh. Org. Khirm. 1988, 24(2), 453-4 corresponding to V. A. Chervonyi et al., J. Org. Chem. USSR (Engl. transl.) 1988, 24, 401. The latter publication describes, for example, the preparation of 4-tolylsulfonyl-5-dimethylamino-2-phenyl-1,3-oxazole.
The invention was based on the object of finding sulfonyloxazolamines with valuable properties. In particular it was important to find pharmacologically active sulfonyloxazolamines.
The object is achieved by compounds of the general formula I described hereinbefore and physiologically acceptable salts or solvates thereof.
It was found that the compounds of the formula I and their pharmacologically active salts surprisingly have a selective affinity to 5-HT6 receptors, together with good tolerability, and they are therefore 5-HT6 receptor ligands. They exhibit 5-HT6-antagonistic or 5-HT6-agonistic actions.
5-HT6 receptors form a subfamily of 5-HT receptors. The neurotransmitter 5-hydroxytryptamine (5-HT), also known as serotonin, is an important regulating neurotransmitter in the brain, whose actions are assisted by a family of receptors which, at the current level of knowledge, contains 13 G protein-coupled receptors and an ion channel. The group of G protein-coupled receptors also includes the 5-HTG receptors. Some representatives have been cloned and to some extent histologically and biochemically investigated (see, for example, Kohen et al. (1996) J. Neurochem 66, 47-56; Ruart et al. (1993), 193, 268-76).
The greatest density of the serotonin 5-HT6 receptors in the brain is found in the olfactory tubercle, in the nucleus accumbens, in the striatum, in the dentate gyrus and in the CA1-3 regions of the hippocampus. These regions are involved to a particular extent in psychiatric disorders such as, for example, schizophrenia or depression. Moreover, it is known from animal experiments that the administration of 5-HT6 antisense oligonucleotides causes a behavioural syndrome which corresponds to that of dopamine agonists. Furthermore, hyperactivity of the dopaminergic neurotransmitter system in schizophrenia (dopamine hypothesis of schizophrenia) is pathophysiologically confirmed. However, dysfunctions of the dopamine system in various forms of depression have been demonstrated. Of the established or alternatively newer therapeutics which are employed in clinical practice for the treatment of these psychiatric disorders, a large number moreover bind to the 5-HT6 receptor. The atypical neuroleptics (e.g. clozapine) and the tricyclic antidepressants (e.g. amitriptyline) may be mentioned here in particular.
Moreover, it was found in animal experimental investigations that 5-HT6 receptors in the brain control cholinergic neurotransmission. Cholinergics are employed in disorders with memory disturbances such as, for example, Alzheimer""s disease.
For these reasons, it can be concluded that there is an involvement of the 5-HT6 receptor in psychiatric and neurological disorders such as, especially, schizophrenia, depression and Alzheimer""s.
The compounds of the formula I and their physiologically acceptable salts are therefore suitable as therapeutic active compounds for disorders of the central nervous system. The compounds of the formula I and physiologically acceptable salts or solvates thereof are particularly suitable for the treatment of psychoses, schizophrenia, manic depression (B. L. Roth et al., J. Pharmacol. Exp. Ther. 1994, 268, 1403-1410), depression (D. R. Sibley et al., Mol. Pharmacol. 1993, 43, 320-327), neurological disorders (A. Bourson et al., J. Pharmacol. Exp. Ther. 1995, 274, 173-180), memory disorders, Parkinson""s disease, amyotrophic lateral sclerosis, Alzheimer""s disease, Huntington""s disease (A. J. Sleight et al., Neurotransmitters 1995, 11, 1-5), bulimia, anorexia nervosa or other eating disorders, compulsive acts or of premenstrual syndrome. Solvates of the compounds of the formula I are understood as meaning adducts of xe2x80x9cinertxe2x80x9d solvent molecules to the compounds of the formula I, which are formed on account of their mutual force of attraction. Solvates are, for example, mono- or dehydrates or alcoholates.
For all radicals which occur one or more times it holds true that their meanings are independent of one another.
R3 and R4 are preferably and independently of one another methyl, methoxy, chlorine and bromine or hydrogen. 
is preferably phenyl, o-, m- or p-methylphenyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-aminophenyl, o-, m- or p-N,N-dimethylaminophenyl, o-, m- or p-nitrophenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m-, p-trifluoromethylphenyl, o-, m- or p-fluorophenyl, o-, m- or p-chlorophenyl, o-, m- or p-bromophenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dihydroxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl.
Particularly preferred for 
is phenyl, o- or p-methylphenyl, o- or p-chlorophenyl, p-bromophenyl, p-methoxyphenyl or 2,4-dichlorophenyl.
xe2x80x94Hal is fluorine, chlorine or bromine.
R1 and R2 together may also form a mononuclear saturated heterocycle having from 1 to 2 N, O and/or S atoms.
This heterocycle is preferably tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or 4-imidazolyl, tetrahydro-1-, -3- or 4-pyrazolyl, 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-perhydroazepinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl or 1-, 2- or 3-piperazinyl, 1-Piperidinyl or 4-morpholinyl is particularly preferred.
Compounds in which R1 is H are preferred.
Furthermore, compounds of the general formula I in which R2 is R6 are preferred.
Moreover, R3 and/or R4 are preferably H.
R5 is preferably 2-furyl, 2-thienyl or 3- or 4-pyridyl.
R6 is linear or branched, and has 1 to 6, preferably 1, 2, 3 or 4, C atoms. R6 is preferably methyl, furthermore ethyl, propyl, butyl, isobutyl, sec-butyl or tert-butyl, in addition also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl or hexyl.
Methyl is particularly preferred.
Alkenyl is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, in addition is preferably 4-pentenyl, isopentenyl or 5-hexenyl. Allyl is particularly preferred for alkenyl.
A base of the general formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation. For this reaction, suitable acids are in particular those which yield physiologically acceptable salts. Thus inorganic acids can be used, e.g. sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g. formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and disulfonic acids or lauryl sulfuric acid. Salts with physiologically unacceptable acids, e.g. picrates, can be used for the isolation and/or purification of the compounds of the formula I.
The invention further relates to the use of the compounds according to the general formula I and physiologically acceptable salts and solvates thereof for preparing medicaments, in particular for preparing anticonvulsants, nootropics, anti-inflammatories, neuroprotectants and cerebroprotectants and for preparing medicaments for the treatment of diseases of the central nervous system, in particular for the treatment of schizophrenia, depression, pathological anxiety states, epilepsy, pathological memory disorders such as Alzheimer""s disease, neurological disorders, amyotrophic lateral scleroses, Huntington""s disease, disorders of the gastrointestinal tract, functional gastropathy, irritable bowel syndrome, bulimia, anorexia nervosa, compulsive acts (obsessive-compulsive disorder, OCD), premenstrual syndrome, migraine, drug addictions, sleeping disorders and/or for the treatment of head and spinal injuries.
The substances according to the invention are as a rule administered here in a dose of preferably between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit. The daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight. The specific dose for each patient, however, depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, and sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred.
The compounds of the general formula I may also be employed as pesticides.
The invention further relates to a pharmaceutical preparation comprising at least one compound according to the general formula I and physiologically acceptable salts and solvates thereof and, where appropriate, vehicles and/or excipients.
These preparations can be used as pharmaceuticals in human or veterinary medicine.
Possible vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral), or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petroleum jelly. Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, in particular, are used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, in addition suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application. The novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations. The preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, buffer substances, colourants, flavourings and/or one or more other active compounds, e.g. one or more vitamins.
For the subject of the invention, of the therapeutic active compounds of the formula I or their physiologically acceptable salts or solvates, of the use of the compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds or of the production of a pharmaceutical preparation for the treatment of disorders of the central nervous system, all the more preferred are compounds of the formula I, the more radicals have one of the preferred or particularly preferred meanings mentioned hereinbefore.
The invention further relates to the preparation of compounds of the general formula I, where R1R2NH is reacted with compounds of the general formula II or III.
The invention also relates to the compounds of the general formula II: 
where
R3 and R4 independently of one another are H, xe2x80x94R6, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94Hal, xe2x80x94OH, xe2x80x94Oxe2x80x94R6, xe2x80x94NH2, xe2x80x94NHxe2x80x94R6 orxe2x80x94N(R6)2,
R5 is a 5- or 6-membered, saturated or unsaturated heterocycle having one or two nitrogen, oxygen and/or sulfur atoms which may be mono- or disubstituted by R6, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94Hal, xe2x80x94OH, xe2x80x94Oxe2x80x94R6xe2x80x94NH2, xe2x80x94NHxe2x80x94R6 or xe2x80x94N(R6)2, and
R6 is C1-C6-alkyl.
The invention also relates to the compounds of the general formula III 
where
R3 and R4 independently of one another are H, xe2x80x94R6, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94Hal, xe2x80x94OH, xe2x80x94Oxe2x80x94R6, xe2x80x94NH2, xe2x80x94NHxe2x80x94R6 or xe2x80x94N(R6)2,
R5 is a 5- or 6-membered, saturated or unsaturated heterocycle having one or two nitrogen, oxygen and/or sulfur atoms which may be mono- or disubstituted by R6, xe2x80x94CF3, xe2x80x94NO2, xe2x80x94Hal, xe2x80x94OH, xe2x80x94Oxe2x80x94R6, xe2x80x94NH2, xe2x80x94NHxe2x80x94R6 or xe2x80x94N(R6)2, and
R6 is C1-C6-alkyl.
The compounds of the general formula I may be synthesized according to the following synthesis scheme (referring to V. A. Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57(4), 415-418; V. A. Chervonyi et al., Zh. Org. Khim. 1988, 24(2), 453-4 corresponding to V. A. Chervonyi et al., J. Org. Chem. USSR (Engl. transl.) 1988, 24, 401; F. Weygand et al. Chem. Ber. 1966, 99, 1944-1956; H. Bxc3x6hrme et al. Arch Pharmaz., 1961, 294, 307-311; A. N. Meldrum and G. M. Vad J. Indian Chem. Soc. 1936, 13, 117-118; D. Z. Barczynski and Z. Eckstein Przem Chem., 1978, 57, 176-177; F. Kasper and H. Bxc3x6ttiger Z. Chem. 1987, 27, 710-71): 
In the synthesis scheme shown beforehand, an amide of the formula R5CONH2 is reacted with chloral resulting in the corresponding xe2x80x9caldehyde ammoniaxe2x80x9d. This is reacted with thionyl chloride resulting in the corresponding tetrachloroethyl derivative. This is subsequently reacted with substituted or unsubstituted sodium benzenesulfinate. This results in a compound of the general formula II or III. Both the compounds of the formula II and the compounds of the formula III react with an amine of the formula R1R2NH with cyclization to give sulfonyloxazolamines of the general formula I.
The suitable reaction conditions of the reactions mentioned from the synthesis scheme are known from the references V. A. Chervonyi et al., Ukr. Khim. Zh. (Russ. Ed.) 1991, 57(4), 415-418 or V. A. Chervonyi et al., Zh. Org. Khim. 1988, 24(2), 453-4 corresponding to V. A. Chervonyi et al., J. Org. Chem. USSR (Engl. transl.) 1988, 24, 401, or from standard works such as, for example, Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart. In this case, use can also be made of variants which are known per se, but not mentioned here in greater detail.
The invention also relates to a process for preparing a compound according to the general formula (II), where
a) R5xe2x80x94CONH2 is added to chloral,
b) the product from a) is chlorinated with thionyl chloride,
c) the product from b) is reacted with an alkali metal salt of a compound of the general formula (IV) 
where R3 and R4 have the meanings listed hereinbefore and Me+ is an alkali metal cation, preferably Na+.